Our research centers on the biology of brain tumors and on the role of PID1, which we recently reported to be a candidate tumor suppressor in gliomas and medulloblastomas. In this exploratory R21 proposal we will focus on glioblastoma (GBM), the most common primary malignant brain tumor in humans. We showed that PID1 overexpression was growth-inhibitory in cell lines from GBM and that higher PID1 mRNA levels were correlated with longer patient overall survival. Here we will examine the role of PID1 as a sensitizer of GBM to therapy and examine its molecular mechanism. PID1 is a phosphotyrosine binding (PTB) domain-containing protein discovered in 2006. PID1 functions in obesity-mediated insulin resistance via inhibition of insulin signaling, is linked to Alzheimer's disease, and as we showed, has tumor-suppressive effects in glioma and medulloblastoma brain tumors by an unknown mechanism. Ongoing experiments find that PID1 sensitizes glioma cells to chemotherapy and that it is a novel binding partner to a receptor with critical roles in GBM. In this Exploratory R21 proposal we aim to understand the mechanism by which PID1 sensitizes GBM to chemotherapy and inhibits GBM growth. Our Aims will 1) determine the mechanism and characteristics of PID1 interactions with the receptor and effect on signaling and proliferation in GBM, and 2) investigate the sensitization of GBM to chemotherapy in vitro and in vivo. Our recent work highlights the significance of PID1 in brain tumors, pointing to a potential inhibitory and/or therapy-sensitizing role of PID1. The significance of our mechanistic findings will likely extend to other diseases, as PID1 is relevant in obesity, insulin resistance, and Alzheimer's disease. The main innovative aspects of this work include the finding of PID1 as a sensitizer of GBM to chemotherapy and the novel mechanism we will uncover. These results will provide the basis to design modalities that will sensitize GBM to therapy.